Organic Letters
Letter
(15) (a) Yeung, P. Y.; Chung, C. H.; Kwong, F. Y. Org. Lett. 2011,
13, 2912. (b) So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. - Eur. J. 2011,
17, 761. (c) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett.
2007, 9, 3469. (d) Choy, P. Y.; Luk, K. C.; Wu, Y.; So, C. M.; Wang,
L.-L.; Kwong, F. Y. J. Org. Chem. 2015, 80, 1457. (e) Yuen, O. Y.;
Charoensak, M.; So, C. M.; Kuhakarn, C.; Kwong, F. Y. Chem. - Asian
J. 2015, 10, 857. For a book chapter, see: (f) Wu, Y.; Wang, J.; Kwong,
F. Y. In Cross Coupling and Heck-Type Reactions 2, Carbon−Heteroatom
Cross-Coupling and C−C Cross Coupling of Acidic C−H Nucleophiles,
Science of Synthesis; Wolfe, J. P., Ed.; Georg Thieme Verlag: Stuttgart,
2013; pp 621−646.
(16) For a pertinent review of cross coupling of ArCl, see: (a) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. For a reference
book, see: (b) Metal-Catalyzed Cross-Coupling Reasctions; 2nd ed.; A.
de Meijere, Diederich, F., Eds.; Wiley−VCH, Weinheim, 2004; Vols.
1−2.
(17) In general, the increase of the steric bulkiness of the alkyl group
(e.g., from Cy to t-Bu group) would also increase the electron richness
of the −PR2 group. The first steric factor certainly favors the RE
process, but the second electronic factor would slow the RE. These
two aspects cannot be handled separately from a single −PR2 group.
(18) The indicated C-3 position of indole is estimated to be 1013
times more reactive than benzene for electrophilic attack; see: Laws, A.
P.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, 591.
(19) For design of an electron-deficient phosphine ligand that is fit
for the reductive elimination, see: (a) Zhang, H.; Luo, X.; Wongkhan,
K.; Duan, H.; Li, Q.; Xhu, L.; Wang, J.; Batsanov, A. S.; Howard, J. A.
K.; Marder, T. B.; Lei, A. Chem. - Eur. J. 2009, 15, 3823. For a relevant
example of phosphine ligands containing aryl rings with electron-
withdrawing substituent facilitate a faster C−N reductive elimination,
see: (b) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
REFERENCES
■
(1) For recent reviews, see: (a) Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010,
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(d) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49,
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J.; Colacot, T. J. Eur. J. Org. Chem. 2015, 2015, 38. For initial
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Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (g) Palucki, M.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 11108. (h) Hamann, B. C.; Hartwig,
J. F. J. Am. Chem. Soc. 1997, 119, 12382. (i) Muratake, H.; Natsume,
M. Tetrahedron Lett. 1997, 38, 7581.
(2) (a) Prasada Rao, L. V. S.; Abraham, T.; Neelima, K.-J.; Vidya
Ganapati, K. IN2009MU01140, 2010. (b) Naresh, K.; George, I.
WO2007085042A1, 2007. (c) Parry, N. J.; O’Keeffe, J. C.; Smith, C. F.
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(f) Vitale, P.; Tacconelli, S.; Perrone, M. G.; Malerba, P.; Simone, L.;
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(3) Marsden, S. P. In Cross Coupling and Heck-Type Reactions 2,
Carbon−Heteroatom Cross-Coupling and C−C Cross Coupling of Acidic
C−H Nucleophiles, Science of Synthesis; Wolfe, J. P., Ed.; Georg Thieme
Verlag: Stuttgart, 2013; pp 565−620.
(4) For multiple arylation of acetone with aryl halides, see the
2010, 132, 3676. For another approach that eliminates the use of
benzylic proton, see: (b) Liu, C.; Deng, Y.; Wang, J.; Yang, Y.; Tang,
S.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 7337.
(20) For a recent reference describing the specially designed biaryl-
type phosphine ligand for a difficult RE process, see: Li, C.; Chen, T.;
Li, B.; Xiao, G.; Tang, W. Angew. Chem., Int. Ed. 2015, 54, 3792.
(21) Example 2e represents the most sterically bulky ArCl substrate
for monoarylation of acetone.
(22) To investigate the possible influence of nitrile group
coordination in this catalysis, an additional experiment was conducted.
When 1 equiv of PhCN (0.5 mmol) was added to the acetone
arylation of 2a (Scheme 2), the product yield was dropped from 87%
to 23%, with 70% ArCl unreacted (as judged by calibrated GC−FID
analysis).
(5) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
5816. (b) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
(6) (a) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc.
2011, 133, 5194. (b) Rotta-Loria, N. L.; Borzenko, A.; Alsabeh, P. G.;
Lavery, C. B.; Stradiotto, M. Adv. Synth. Catal. 2015, 357, 100.
(7) Li, P.; Lu, B.; Fu, C.; Ma, S. Adv. Synth. Catal. 2013, 355, 1255.
̈
(8) Gabler, C.; Korb, M.; Schaarschmidt, D.; Hildebrandt, A.; Lang,
̈
H. Adv. Synth. Catal. 2014, 356, 2979.
(9) Apart from aryl halides, aryl imidazolylsuflonates were found to
be applicable substrates; see: Ackermann, L.; Mehta, V. P. Chem. - Eur.
J. 2012, 18, 10230.
(23) Previous literature reported the benzyl-protected indole for the
α-arylation process. See ref 6a.
(10) CyPF-tBu = (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]
ethyldi-tert-butylphosphine. During the completion of our exper-
imental works, a related paper appeared; see: MacQueen, P. M.;
Chisholm, A. J.; Hargreaves, B. K. V.; Stradiotto, M. Chem. - Eur. J.
2015, 21, 11006. The aryl chloride scope was found to be moderate.
Only p-CF3-p-C6H4-p-C6H4Cl and p-CN-p-C6H4-p-C6H4Cl with 10
mol % Pd catalyst were found applicable. No direct electron-deficient
−CF3- and −CN-containing substrates were reported.
(11) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
1473. (b) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360. (c) Ehrentraut, A.; Zapf, A.; Beller, M.
Adv. Synth. Catal. 2002, 344, 209.
(24) Donati, G.; Paludetto, R. Catal. Today 1997, 34, 483.
(25) It is preferable to use a Schlenk tube in small-scale reactions.
However, when the scale is increased, problems will be generated. On
a 100 mmol scale, a 4 L Schlenk flask is required for this synthesis.
(26) A three-necked round-bottom flask equipped with thermometer,
rubber septum, and water condenser was used as the vessel for this
acetone monoarylation reaction.
(27) The reaction temperature was measured to be about 60 °C.
(28) Stradiotto reported the RE is the rate-limiting step. For the
initial rate study using a Pd/Mor-DalPhos system, see the Supporting
Information of ref 6a.
(12) For examples of the relationship between ligand and substrate
scope of the α-arylation reaction, see: (a) Lee, S.; Hartwig, J. F. J. Org.
Chem. 2001, 66, 3402. For the metal factor (Pd and Ni, with the same
phosphine ligand) controlling the reaction efficiency (Pd for electron-
rich/neutral substrates while Ni for electron-poor substrates), see:
(b) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.
(13) (a) Jia, T.; Bellomo, A.; Baina, K. E. L.; Dreher, S. D.; Walsh, P.
J. J. Am. Chem. Soc. 2013, 135, 3740. (b) Zheng, B.; Jia, T.; Walsh, P.
Org. Lett. 2013, 15, 1690. (c) Zheng, B.; Jia, T.; Walsh, P. Org. Lett.
2013, 15, 4190.
(29) Ligand cost and catalyst loading become two of the most
important factors in production-scale catalysis; see: Schlummer, B.;
Scholz, U. Adv. Synth. Catal. 2004, 346, 1599. In view of cost-
effectiveness, the new ligand L1 features the use of the inexpensive
−PPh2 group (precludes the incorporation of relatively expensive
−PR(alkyl)2 group). According to the 2014 Aldrich catalog, ClPPh2
(337.5 USD/500g) is approximately 80 times less expensive than
ClPCy2 (271.5 USD/5g) and 378 times cheaper than ClPAd2 (255.5
USD/g). Chlorodiferrocenylphosphine is not commercially available.
(14) (a) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963.
(b) Wong, S. M.; Yuen, O. Y.; Choy, P. Y.; Kwong, F. Y. Coord. Chem.
Rev. 2015, 293−294, 158. (c) Chow, W. K.; Yuen, O. Y.; Choy, P. Y.;
So, C. M.; Lau, C. P.; Wong, W. T.; Kwong, F. Y. RSC Adv. 2013, 3,
12518.
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